12-hydroxystearic acid esters of 21-hydroxy steroids of the pregnane series



United States Patent Ofilice 3,059,001 Patented Oct. 16, 1962IZ-HYDROXYSTEARIC ACID ESTERS F ZIt-HY- DROXY STEROIDS OF THE PREGNANEfiERES Werner Haede, Hofheim (Taunus), Leonhard Middendorf,

Frankfurt am Main, and Werner Fritsch, Neuenhain (Taunus), Germany,assignors to Farhwerke Hoechst Akfiengesellschaft vormals Meister Lucius& Briining,

Frankfurt am Main, Germany, a corporation of Germany N0 Drawing. FiledSept. 12, 1960, Ser. No. 55,132

4 Claims. (Cl. 260397.45)

We have found that novel esters of hydroxycarboxylic acids of thepregnane series which exhibit an excellent solubility in oil can beobtained by reacting derivatives of compounds of the pregnane seriesthat are substituted in 2l-position, with alkali metal salts ofhydroxycarboxylic acids in the presence of an inert organic solvent orsuspending agent.

The novel hydroxycarboxylic acid esters are distinguished by anextraordinarily high solubility in oil; by reason of this property theycan be clinically used as depot preparations. As is shown in thefollowing comparative table, the products of the present invention areseveral times more soluble in vegetable oils than the esters knownhitherto.

The alkali metal salts of the hydroxycarboxylic acids used in theprocess of the present invention can be obtained by mixing an alkalimetal alcoholate in a solvent (for example, methanol, or ethanol) at amolecular proportion of 1:1 with the corresponding hydroxycarboxylicacid and precipitating the alkali metal salt from this reaction mixtureby the addition of an inert solvent for, example, acetone, benzene,tetrahydrofurane or dioxane. The alkali metal salt is suitably welldried in the vacuum and pulverized in a ball mill.

As compounds of the preguane series that are substituted in 2l-position,there enter into consideration, for example, the 21-halides and thehalide-like sulfonates such as the 21-mesylate and 2l-tosylate andsimilar compodn d? As regards the halides, the iodides are preferablyused for the reaction, but the chlorides and bromides are also suitable.It is also possible to add a small quantity of sodium iodide to thechlorides or bromides and thus intermediarily produce the correspondingiodide. In particular, the following compounds are mentioned by way ofexample as starting substance, the term 21-ha1ogen designating one ofthe halogen atoms mentioned before or one of the halide-like sulfonateradicals:

A -pregnene-35-ol-2l-halogen-ZO-one A -pregnene-2 l-halogen-3,20-dione A-pregnene-l7-ol-21-ha1ogen-3,11,20-trione A -pregnene-l 1 B,l7a-diol-21-halogen-3,20-dione.

As hydroxycarboxylic acids there may be used aliphatic hydroxycarboxylicacids containing 14 to 22 C- atoms, preferably l2-hydroxystearic acidand ricinoleic acid. For the reaction of the 21-den'vatives of thepregnane series according to the process of the present invention, thereare suitable the salts of the indicated hydroxycarboxylic acids with allalkali metals, but in general it is preferred to use the potassium orsodium salts.

The esterification is suitably eflfected by dissolving or suspending thementioned starting substances in acetone, tetrahydrofurane,dimethylformamide or similar inert solvents, and by heating the wholetogether with an alkali metal salt of a hydroxycarboxylic acid withstirring. It is preferred to use the alkali metal salt in excess and toadd an excess quantity of hydroxycarboxylic acid in order to obtain aneutral reaction medium.

The following examples serve to illustrate the invention but they arenot intended to limit it thereto:

EXAIWPLE 1 A -Pregnene-3 8,21 -Di0l-20-One-12 H ydroxystearate- (21 30grams of A -pregnene-3/8-ol-21-iodine-20-one are dissolved in 400 cc. ofacetone and, after addition of 35 grams of the potassium salt ofl2-hydroxystearic acid and 1.5 grams of l2-hydroxystearic acid, thewhole is refluxed, While stirring, for 8 hours. The reaction mixture isevaporated to dryness under slightly reduced pressure and then extractedwith methylene chloride. The methylene chloride solution is shaken withdilute soda solution, dried over sodium sulfate and evaporated todryness. The residue is recrystallized from 50 cc. of acetone.

The A -pregnene-3 8,2l-diol-ZO-one-12-hydroxystearate- (21) is obtainedin a very good yield.

The product melts at 6569 C.

EXAMPLE 2 A -Pregn sane-3,6,2]-Di0l-20-One-Ricinoleate- (21 28 grams ofA -pregnene-3 8,ol-2l-iodine-ZO-one are dissolved in 200 cc. of acetoneand after addition of 28 grams of the potassium salt of ricinoleic acidand 2 grams of ricinoleic acid, the whole is refluxed for 8 hours, withstirring. The product is worked up as described in Example 1.

From cc. of ethanol, there is obtained a wax-like product melting at54-57" C.

EXAMPLE 3 -Pregnene-21-Ol-3,20-Di0ne-12'-Hydroxystearate-(2I 30 grams ofA -pregnene-21-chlorine-3,2O-dione are dissolved in 300 cc. of acetoneand refluxed, while stirring, for 6 hours together with 35 grams of thepotassium salt of l2-hydroxystearic acid, 1.5 grams of l2-hydroxystearicacid and 1.5 grams of sodium iodide. The reaction mixture is worked upin the manner described in Example 1. However, the residue does notcrystallize. For purification, the residue is dissolved in ether and thesolution is allowed to pass through a column of 30 grams of acidicaluminum oxide.

After evaporation of the ether and heating of the residue under reducedpressure, there is obtained the Apregnene-2l-ol-3,20-dione-12'-hydroxystearatea(2l) in the form of anoil.

EXAMPLE '4: -Pregnene-1 70:,21-Di0l-3,11,20-Tri0ne-12- H ydroxystearate-(21 2 grams of A -pregnene-17a-ol-21-chlorine-3,ll,20-trione arerefluxed, while stirring, for 6 hours with 3 grams of the potassium saltof l2-hydroxystearic acid, mg. of sodium iodide and 20 mg. ofhydroxystearic acid in 40 cc. of acetone. The reaction solution isfiltered with An intimate mixture of 4.52 grams of 6-methyl-Apregnadiene-l1B,17cx-21-ltriol-3,20-dione-21 mesylate and 4.23 grams ofthe potassium salt of 12'-hydroxystearic acid are suspended in 50 ml. ofdimethylformamide and heated for 2 /2 hours, While stirring, to 60 C.and in an atmosphere of nitrogen. The reaction mixture is then stirredinto 300 ml. Water. The ester is extracted with a mixture of methylenechloride and ether and, after evaporation of the solvent, brought tocrystallize by adding petroleum ether. There are thus obtained 6.1 gramsof A -pregnadiene-11B,17a 21-triol-3,20 dione-12'-hydroxystearate-(Zl)having a melting point of 87 C. (Kofler heater). 90 milligrams of thehydroxystearate dissolve at 23 C. in 1 ml. of a mixture of 6.5 parts ofsesame-oil and 3.5 parts of castor-oil.

. and 4.20 grams of the potassium salt of 12'-hydroxystearic acid arewell mixed and added with 50 ml. of dimethylformamide and then heatedfor 3% hours to C., While stirring, under anitrogen atmosphere. Afterthe reaction mixture has cooledtit is stirred into 300 ml. of Water. Theester so formed is extracted three times With each time 25 ml. of ether.After drying over sodium sulfate, the extract is concentrated todryness, first under re duced pressure and finally in a high vacuum, atC. There are obtained 5.7 grams of A -pregnene-21-ol-3,20-dione-12'-hydroxystearate-(2l) in the form of an oil. The compound ismiscible to an almost unlimited degree with the mixture of sesame andcastor-oil described in the preceding example.

We claim:

1. A -pregnene-3fi,21 diol-20-one-12'-hydroxystearate- 21 2. A-pregnene-21-o1-3,20 dione-12'-hydroxystearate- (21 3. A-pregnene-17a,21-diol 3,11,20-trione-12-hydroxystearate-( 21 4. A-pregnadiene 115,170: 21-triol-3,20-dione-12- hydroxystearate-(ZlReferences Cited'in the file of this patent UNITED STATES PATENTS Joneset al. Apr. 19, 1960 OTHER REFERENCES 7 1958, page 71 8.

3. $4-PREGNENE-17A,21-DIOL-3,11,20-TRIONE-12''HYDROXYSTERATE-(21).